Candidate gene studies in psychiatric illness

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Abstract

Schizophrenia, bipolar disorder and major depression are common, heritable
neuropsychiatric conditions and yet the source of the inherited risk remains largely
unknown. This thesis focuses on two complementary strategies for identifying and
characterising the genetic component of these illnesses: homozygosity mapping in
consanguineous pedigrees, and genetic and neurobiological investigations of candidate
genes identified by the analysis of structural chromosomal abnormalities carried by
patients with psychiatric diagnoses.
In a family of a cousin marriage, five of six offspring presented with a rare combination
of schizophrenia, sensori-neural hearing impairment and epilepsy. Two loci were located
on chromosomes 22q13 and 2p24-25 where a series of markers were homozygous by
descent (HBD). Five further HBD loci were identified in a second, related family where
four of five offspring had hearing loss. However, there was no overlap of the HBD
intervals in the two families, and sequencing coding regions of candidate genes failed to
identify causative mutations.
A second study investigated the candidate gene ABCA13 identified at a breakpoint
region on chromosome 7 in a patient with schizophrenia who carried a complex
chromosomal rearrangement. Re-sequencing exons encoding the highly conserved
functional domains identified eight potentially pathogenic, rare coding variants. Case
control association studies involving cohorts of schizophrenia, bipolar disorder and
major depression revealed significant associations of these variants with all three clinical
phenotypes, and follow-up in relatives displayed familial inheritance patterns.
Disruption of ABCA13, expressed in human hippocampus and frontal cortex, implicates
aberrant lipid biology as a pathological pathway in mental illness.
A third study focused on GRIK4, a candidate gene previously reported disrupted in a
patient with schizophrenia who carried a chromosome abnormality. A deletion in the 3’UTR of GRIK4, encoding the kainate receptor subunit KA1, was identified as a
protective factor for bipolar disorder. Using post mortem human brain tissue from
control subjects, KA1 protein expression patterns were characterized in the hippocampal
formation, amygdala, frontal cortex and cerebellum. KA1 expression was found
significantly increased in subjects with the protective allele, supporting the hypothesis
that reduced glutamatergic neurotransmission is a risk factor in major psychiatric
illnesses.
Together, these novel discoveries define aspects of the genetic contribution to mental
illness, implicate specific dysfunctional processes and suggest new directions for
research in the quest to find rationally based treatments and preventative strategies for
some of the most common and disabling psychiatric disorders.